Arch Dis Child: first published as 10.1136/adc.47.254.639 on 1 August 1972. Downloaded from

Archives of Disease in Childhood, 1972, 47, 639.

Significance of the Single Umbilical A Clinical, Radiological, Chromosomal, and Dermatoglyphic Study R. F. VLIETINCK, M. THIERY, E. ORYE, A. DE CLERCQ, and P. VAN VAERENBERGH From the Paediatric Clinic and the Department of of the State University of Ghent, Belgium

Vlietinck, R. F., Thiery, M., Orye, E., de Clercq, A., and van Vaerenbergh, P. (1972). Archives of Disease in Childhood, 47, 639. Significance of the single : a clinical, radiological, chromosomal, and dermatoglyphic study. A is present in about 1% of all singletons. It is associated with a wide range of congenital malformations. Chromosomal analysis of our surviving cases gave normal results. Dermatoglyphic patterns were normal, except that the boys showed a three- to fourfold increase in the number of the radial loops on the fingers, and a lowering of the total finger ridge count. Evidence favouring a common non-genetic cause for both a single umbilical artery and the associated malformations is discussed.

Although the absence of one umbilical artery investigation of the karyotype and dermatoglyphs. was first reported a century ago (Hyrtl, 1870), the The mean age at the last examination was 21 months significance of a single umbilical artery (SUA) has (range, 5 months to 31 years). copyright. only been realized since a retrospective study by Benirschke and Brown (1955) showed it was asso- Results ciated with increased incidence of congenital Incidence and mortality. In 29 of the 2572 anomalies. Because most of the investigations on consecutive cords examined (1- 1 %), one umbilical SUA have been made by pathologists, the conclu- artery was lacking. The significance of SUA, and sions drawn may not be applicable to the live infant its association with such factors as birthweight, population. And because most of these studies maternal , and placental pathology have are retrospective, they may also be biased with been discussed elsewhere (de Clercq et al., 1970). respect to the incidence of congenital malformations. Of the 29 children with SUA, 4 were stillborn http://adc.bmj.com/ The present report concerns a prospective study and 2 died neonatally, giving a carried out in a consecutive series of 2572 singletons rate of 21%. Half of the stillborn (2/29: born in the same hospital and followed up over a 7%) showed congenital malformations (Table I). period of several years by means of a planned Of the 23 children with SUA still living, 22 were investigative programme including intravenous given a complete clinical and neurological examina- pyelography (IVP), chromosome patterns, and tion. In one case examination was refused by the

dermatoglyphs. parents; this child had been found to be grossly on October 2, 2021 by guest. Protected normal at birth and showed no malformations at Methods the age of 32 months. Only the 22 children that be discussed here. In this investigation the was studied were fully followed up will in various ways: gross examination of the freshly Five patients had a height that was more than delivered umbilical cord and ; re-examination 2 SDs below the mean, and two exceeded the mean. after fixation for one week in 10% formaldehyde, Consequently, the histogram for length shows a followed by the study of H. and E.-stained paraffin pronounced negative skewness, though for the sections prepared from the middle portion of the cord. whole group no statistically significant difference All children with SUA who succumbed during the from the normal population was found. The perinatal period were necropsied. Follow-up study of distribution for weight and head circumference was the survivors included clinical examination, IVP, and Gaussian, and the values for both were in accor- Received 13 December 1971. dance with those of the normal population. 639 Arch Dis Child: first published as 10.1136/adc.47.254.639 on 1 August 1972. Downloaded from 640 Vlietinck, Thiery, Orye, de Clercq, and van Vaerenbergh TABLE I Congenital Malformations with Single Umbilical Artery, Present Series

Grade Frequency Type Outcome {1 Internal hydrocephaly 2/29 = 7% 2/9%<1 Coarctation ofaorta and polycystic kidneys }tlbrStillborn Major (14%) 1 Supravalvular |2/2222= 9% {V1 Talipes Living Minor 1/19 = 5% 1 Renal duplicated 4/22 = 18% 4 Tuberous haemangioma J Total 9

Psychomotor development was evaluated. All the with SUA the total finger ridge count had a mean children except one with a post-meningitis hydro- of 91 5 as compared with 145 for the normal cephalus passed their milestones at the normal age. controls (P <0 05). All but two of the boys had At physical examination, two children (2/22 = total counts below 100, because SUA males show 9%) had disabling malformations (Table I): one less than half the normal frequency of whorls. boy showed a supravalvular aortic stenosis, not The frequency of radial loops was three times associated with idiopathic hypercalcaemia, the normal. In the girls, the total finger ridge count other, also a boy, had congenital clubfeet at birth; was higher (156 5) than in normal controls (125), this child contracted bacterial meningitis during but this difference is not statistically significant. his first month, became hydrocephalic, and showed Only one girl had a value below 140. None of the mental retardation. Four children (4/22 = 18%) girls had any arch, a pattern normally occurring had superficial angiomatous naevi ('strawberry more frequently in girls than in boys. Females naevi') measuring more than 3 x 1 cm. In two with SUA had a fourfold frequency of radial loops copyright. of them the lesions were multiple, bilateral, and as compared to normal controls. The palm prints distributed over the chest, , and hands showed normal flexion creases; none of the patients (Table I). had either simian or Sidney lines. The maximal atd-angle was normal, as was the AD-index. The . Of the 22 living children, an IVP digital triradii and main lines were all present and was undertaken in 19; all but one had a normal showed a normal course. The interdigital, hypo- configuration of the kidneys and urine collecting thenar, and thenar areas did not show any unusual system. This patient (1/19 5%) had complete pattern. duplication of the left renal pelvis (Table I). http://adc.bmj.com/ In half of the patients accurate measurement of Discussion the renal size could be made, and this was normal, As can be seen from Table I, the total incidence with a mean 0 * 5 standard error below the mean of of congenital malformations differs significantly controls. from that of the normal population. The wide Thus, the overall incidence of diagnosed major ranges found in the literature are probably attribu- congenital malformations amount to 4/29 or 14%. table to at least two biases. Because one group of

authors obtained their material from a department on October 2, 2021 by guest. Protected Karyotype and dermatoglyphs. Blood lym- of pathology, selection must have increased the phocytes were successfully cultured in 19 cases. For incidence of malformations reported. Prospective each patient, 20 well-spread mitoses were counted studies generally yield correct incidences for the and 5 were karyotyped. All these patients dis- various malformations diagnosed at birth. But played 46 normal chromosomes, with no structural because an important fraction of the anomalies anomalies or excessive breaks or recombinations.* only become manifest later in life, a more exhaustive In 18 children (10 boys, 8 girls) the dermato- examination, including radiological methods, in- glyphs were analysed. The fingerprints of children creases the incidence. A systematic investigation born with SUA differ significantly from those of the urinary tract by IVP was performed by found in the normal population. In male patients Feingold, Fine, and Ingall (1964), who found 8/24 abnormal Beh- *Since the completion of this study, two further patients were (33%) urograms. VanLeeuwen, investigated with the same results. ringer, and Glenn (1967) obtained a normal IVP Arch Dis Child: first published as 10.1136/adc.47.254.639 on 1 August 1972. Downloaded from

Significance of the Single Umbilical Artery 641 in all of the 6 children examined, and Schroyer with SUA (2 4% according to Javert, 1957, and (1967) found only 3 minor deviations from the Thomas, 1963), it can be shown that of 100 fetuses normal in 26 urograms. In our study we have with SUA reaching term, 11 are born dead and combined cord examination with long-term follow- another 17 die within the first year; thus, only up (up to 3*5 years) and with specialized examina- 72% remain alive. Of the latter, one-fourth (18%) tions of all the children with SUA born in one are malformed, which leaves a figure of 54% hospital during a period of time. healthy children. Freely quoting Faierman (1960): On the basis of data in the literature (Fig. 1A, of every three children in whom SUA is diagnosed Tables II and III), and without taking into account but who show no obvious malformation at birth, the fetal wastage due to spontaneous abortions one harbours a lethal but unrecognized anomaly, and one has a malformation correctable surgically; A B only one out of three is normal. According to our own results (Fig. 1B), 21% of the children die (stillborn 14%, death in first year 7%) and 14% have congenital malformations, sufficiently severe to cause disability. Most authors agree that concomitant congenital anomalies lack organ specificity. The sireniform monster and the acardiacus, the most severe manifestations of this syndrome, are invariably associated with SUA (Schatz, 1898-1900; Ballan- tyne, 1904; Kampmeier, 1927; Hendry and Kohler, Stillborn 1956; Slipka and Kocova, 1970), while First year disease, urogenital abnormalities, and skeletal * Congenital malformation malformations are common. Though of minor importance, tuberous haemangioma has shown a

FIG.-Frequency of mortality and of congenital malforma- copyright. tions in single umbilical artery. A, data reported in the surprisingly high incidence in our SUA group, literature; B, present series. an association not previously reported. 3LE II Congenital Malformations with Single Umbilical Artery, Reported in Literature*

Type of Study All SUA Studies Prospective Retrospective http://adc.bmj.com/ Total No. of Cases % Total No of Cases % Total No. of Cases % Living 396 100 25 *0 (28) (2) (7 1) 483 121 25 *0 Dead 89 48 54-0 141 75 53-0 250 123 49*5 Total 487 148 30 5 169 77 45 5 733 244 33 7

*A complete reference list can be obtained from one of the authors (R.F.V.). TABLE III on October 2, 2021 by guest. Protected Mortality in Single Umbilical Artery, as Reported in Literature*

Type of Study All SUA Studies (733 Cases) Prospective (487 Cases) Retrospective (169 Cases)

,, ,~ No. of Cases % No. of Cases % 56 9 *5 32 19*0 Died 43 8*7 28 16-6 Total 99 18*2 60 35*6 1 1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ *A complete reference list can be obtained from one of the authors (R.F.V.). Arch Dis Child: first published as 10.1136/adc.47.254.639 on 1 August 1972. Downloaded from

642 Vlietinck, Thiery, Orye, de Clercq, and van Vaerenbergh Little is known about the aetiology of the SUA Dellenbach, P., Leissner, P., Philippe, E., Gillet, J. Y., and Muller, P. (1968). Artere ombilicale unique, insertion velamenteuse syndrome. A chromosomal aetiology has been du cordon ombilical et malformations foetales. Revue Francaise suggested on the basis of (1) the high fetal wastage de Gynecologie et d'Obstetrique, 63, 603. Dunn, P. M., Fisher, A. M., and Kohler, H. G. (1962). Phocomelia. (Javert, 1957; Bourne and Benirschke, 1960; American Journal of Obstetrics and Gynecology, 84, 348. Thomas, 1963); (2) the wide variety of severe Faierman, E. (1960). The significance of one umbilical artery. congenital malformations; and (3) the reported Archives of Disease in Childhood, 35, 285. Fasolis, S., and Okely, S. (1961). Agenesia dell'arteria ombelicale association of SUA with trisomy (especially destra in entrambi gli individui di coppia gemellare. Folia trisomy-18 and -13, but also mongolism) and with Hereditaria et Pathologica, 10, 115. Feingold, M., Fine, R. N., and Ingail, D. (1964). Intravenous gonadal dysgenesis (Richart and Benirschke, 1958; pyelography in infants with single umbilical artery. New German et al., 1962; Uchida, Bowman, and Wang, England Journal of , 270, 1178. Fujikura, T. (1964). Single umbilical artery and congenital mal- 1962; Lewis, 1962; Feingold et al., 1964; Gustavson, formations. American Journal of Obstetrics and Gynecology, 1964; Gustavson et al., 1964; Seki and Strauss, 88, 829. 1964; VanLeeuwen et al., 1967; Dellenbach et al., German, J. L., Rankin, J. K., Harrison, P. A., Donovan, D. J., Hogan, W. J., and Beam, A. G. (1962). Autosomal trisomy 1968). As a result of our series of patients where of a group 16-18 chromosome. Journal of , 60, 503. chromosomes and dermatoglyphs were studied, Gustavson, K. H. (1964). Down's Syndrome, pp. 88 and 95. Almqvist and Wiksell, for University of Uppsala Institute for we are led to conclude that SUA is no more than a , Uppsala. fortuitous organ manifestation of trisomy. Gustavson, K. H., Finley, S. C., Finley, W. H., and Jalling, B. Only two instances of familial SUA syndrome (1964). A 4-5/21-22 chromosomal translocation associated with multiple congenital anomalies. Acta Paediatrica, 53, 172. (Adler, Lewenthal, and Ben-Adereth, 1963; Dellen- Hack, M., Brish, M., Serr, D. M., Insler, V., and Lunenfeld, B. bach et al., 1968) are on record. Of the twins (1970). Outcome of after induced ovulation. Journal of the American Medical Association, 211, 791. studied, all but three cases (Fasolis and Okely, 1961; Hendry, D. W., and Kohler, H. G. (1956). . Journal Fujikura, 1964; Slipka and Kocova', 1970) were of Obstetrics and of the British Empire, 63, 865. Hyrtl, J. (1870). Die Blutgefasse der menschlichen Nachgeburt in found to be discordant irrespective of their zygosity. normalen und abnormen Verhaltnissen. W. Braumiiller, Vienna. Numerous authors have found no consanguinity Javert, C. T. (1957). Spontaneous and Habitual Abortion. Blaki- among the SUA families (Bourne and Benirschke, ston, New York. Kajii, T., Shinohara, M., Kikuchi, K., Dohmen, S., and Akichika, 1960), as has been our own experience. The M. (1963). Thalidomide and the umbilical artery. (Letter.) association of SUA with thalidomide embryopathy Lancet, 2, 889. copyright. Kampmeier, 0. F. (1927). On sireniform monsters, with a con- (Russell and McKichan, 1962; Dunn, Fisher, and sideration of the causation and the predominance of the male Kohler, 1962; Thomas, 1963; Kajii et al., 1963) sex among them. Anatomical Record, 34-35, 365. children to Lewis, A. J. (1962). Autosomal trisomy. (Letter.) Lancet, 1, 866. and the prevalence of with SUA born Richart, R., and Benirschke, K. (1958). Gonadal dysgenesis in a women in whom ovulation has been induced (Hack newborn infant. New England Journal of Medicine, 258, 974. et al., 1970) argues for a teratogenic aetiology of Russell, C. S., and McKichan, M. D. (1962). Thalidomide and congenital anomalies. (Letter.) Lancet, 1, 429. the syndrome. The wide variety of affected organs Schatz, F. (1898-1900). Die Gefassverbindungen der Placentakreis- indicates that there is no critical embryonic stage laufe eineiiger Zwillinge, ihre Entwicklung und ihre Folge. (Benirschke and Brown, 1955; Faierman, 1960; Archiv fur Gyndkologie, 55, 485; 58, 1; 60, 81, 201, 559. Schroyer, W. W. (1967). Single umbilical artery. A research for http://adc.bmj.com/ Bourne and Benirschke, 1960), and that the factor(s) associated renal agenesis. Personal communication to Ben- must be capable of acting very early and probably irschke. In The Pathology of the Human Placenta. By K. Benirschke and S. G. Driscoll. Springer, New York and Berlin. over a long period of time. The disturbances of Seki, M., and Strauss, L. (1964). Absence of one umbilical artery: organogenesis by chromosomal aberrations and by analysis of 60 cases with emphasis on associated developmental aberrations. Archives of Pathology, 78, 446. chemical agents exemplify this. Slipka, J., and Kocova, J. (1970). The absence of one umbilical artery in malformed MZ twins. Acta Geneticae Medicae et REFERENcES Gemellologiae, 19,567. Adler, J., Lewenthal, H., and Ben-Adereth, N. (1963). Absence of Thomas, J. (1963). Die Entwicklung von und Plazenta bei one umbilical artery and its relationship to congenital malforma- Nabelgefassanomalien. Archiv fsir Gynakologie, 198, 216. on October 2, 2021 by guest. Protected tions. (Hebrew.) Harefuah, 65, 286. Uchida, I. A., Bowman, J. M., and Wang, H. C. (1962). The 18- Ballantyne, J. W. (1904). Manual of Antenatal Pathology and trisomy syndrome. 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